Chiral beta-amino carboxamide compounds are frequent constituents of drug candidates, and are also useful in the asymmetric synthesis of biologically active molecules.
The most utilized route to enantiomerically enriched or enantiomerically pure amines to date is optical resolution of the corresponding racemic mixture of the amine. Conventionally, the optical resolution is effected via diastereomeric salts. An alternative to optical resolution via diastereomeric derivatives is biocatalytic kinetic resolution. The disadvantage of optical resolution is a limitation of the theoretical yield to a maximum of 50% from the racemate. The undesired enantiomer has to be either disposed off, or converted back to the racemate and recycled into the production process. The additional working steps for the recycling of the undesired enantiomer are associated with considerable cost and effort.
These disadvantages, which apply in principle to all optical resolution strategies can be avoided by an asymmetric synthesis using prochiral starting compounds. The known asymmetric syntheses using transition metal catalysts, however, often do not achieve the required enantioselectivity. Besides these catalysts, which are generally coordinated with chiral ligands, are often difficult to recover from the reaction mixtures. Furthermore, the use of transition metal catalysts can result in traces of transition metals in the resulting product which is undesirable for pharmaceutical applications.
In the synthesis of chiral amines by use of biocatalysts, product isolation and the recovery and re-use of the enzyme is sometimes associated with difficulties. Other associated drawbacks of biocatalytic reactions include factors such as solubility issues (due to limitations on the type of solvents that can be used), extensive downstream processing operations, and high reaction volumes that may be sometimes required.
Sitagliptin, 7-[(3R)-3-amino-1-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine, a chiral beta-amino carboxamide having the following chemical structure, is an inhibitor of dipeptidyl peptidase-IV.

Sitagliptin is currently marketed as its phosphate salt in the United States under the trade name JANUVIA™. JANUVIA™ is indicated to improve glycemic control in patients with type 2 diabetes mellitus.
U.S. Pat. No. 6,699,871 (Assigned to Merck and Company), discloses a process for preparing sitagliptin. The process disclosed in this patent is very tedious involving several steps and is not suitable for commercial scale manufacture.
WO 2004/085661 (Assigned to Merck and Company) discloses a process for preparing sitagliptin in which (S)-phenylglycine amide is used as a chiral auxiliary to form an intermediate that subsequently provides the desired enantiomer of the amine.
US Patent Application 2008/0058522 (Merck & Company) discloses a process for preparation of enatiomerically enriched beta-amino acid or derivatives by enantioselective hydrogenation of an amine-unprotected prochiral beta-amino acrylic acid or derivative thereof in presence of rhodium metal complexed with a chiral phosphorous ligand. Synthesis of sitagliptin has been exemplified by this method.
US Patent Application 2009/0192326 discloses preparation of sitagliptin by using N-protected 3-amino-4-(2,4,5-trifluorophenyl)butanoic acid alkyl ester as key intermediate, which in turn is obtained by asymmetric reduction of 3-amino-4-(2,4,5-trifluorophenyl)but-2-enoic acid with a rhodium catalyst coordinated with chiral phosphorous ligands.
The processes reported for preparing sitagliptin as mentioned vide supra suffer from drawbacks such as involving use of expensive reagents like platinum oxide or rhodium oxide or metal catalysts with chiral ligands. Some processes require protection and deprotection steps, while some use flammable and expensive solvents. There is therefore a need for a simple, efficient and commercially viable process which does not use expensive reagents or hazardous solvents and for the preparation of the compound of formula I with high chiral purity to the extent of at least 99.9%.
We have now found out that we can achieve with high chiral purity to the extent of at least 99.9% the compound of formula IA-1 through hydrogenolysis of the compound of formula IVA-1, which in turn is obtained by the reaction of compound of formula IIA-1 with a compound of formula IIIA.
